# Patent

## Title
Alkyl-containing 5-acylindolinones, the preparation thereof and their use as medicaments

## Abstract

The present invention relates to alkyl-containing 5-acylindolinones of general formula




wherein R1 to R3 are defined herein, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on protein kinases, particularly an inhibiting effect on the activity of glycogen synthase kinase (GSK-3).

## Background
RELATED APPLICATIONS
This application claims priority benefit under 35 USC 119(e) from U.S. Provisional Application 60/559,471 filed Apr. 5, 2004, which claims benefit from German Application DE 10 2004 012 068.4, filed Mar. 12, 2004.


DESCRIPTION OF THE INVENTION
The present invention relates to new alkyl-containing 5-acylindolinones of general formula




the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable pharmacological properties, for example an inhibiting effect on protein kinases, particularly an inhibiting effect on the activity of glycogen-synthase-kinase (GSK-3), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an altered GSK-3 activity, particularly type I and type II diabetes mellitus, diabetes associated disorders such as diabetic neuropathy, degenerative neurological diseases such as Alzheimer's disease, stroke, neurotraumatic injuries, bipolar disorders, pharmaceutical compositions containing a compound of general formula (I) or a physiologically acceptable salt thereof and processes for the preparation thereof.

In the above formula I

    R1 denotes a straight-chain or branched C1-5-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or
    an aryl group optionally substituted by a fluorine, chlorine or bromine atom,
    
        while by an aryl group is meant a phenyl or naphthyl group,
    
    
    R2 denotes a C1-7-alkyl or C3-7-cycloalkyl group,
    a 5- or 6-membered heteroaryl group with one to three heteroatoms selected from the group N, S and O, while both the heteratoms and the substituents may be identical or different, optionally substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C1-3-alkyl or C1-3-alkoxy groups,
    a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group,
    a phenyl group, to which is anellated another phenyl ring or a 5- or 6-membered heteroaromatic ring with one to three heteroatoms selected from the group N, S and O, while the heteratoms may be identical or different, and the bicyclic group may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C1-3-alkyl or C1-3-alkoxy groups and the substituents may be identical or different, or
    a phenyl group which may be substituted by one to three fluorine, chlorine, bromine or iodine atoms or by one to three C1-3-alkyl, nitro, cyano, amino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, phenylcarbonylamino, C1-3-alkylsulphonylamino, arylsulphonylamino, trifluoromethyl, C1-3alkylsulphonyl, carboxy, C1-3-alkoxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, C1-3-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, hydroxy-carbonyl-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkoxy, C1-3-alkyl-amino-carbonyl-C1-3-alkoxy, carboxy-C1-3-alkoxy, C1-3-alkyloxy-carbonyl-C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonyl-amino-C1-3-alkyl, amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, C1-3-alkyl-carbonyl-amino-C1-3-alkyl, phthalimido, pyrrolyl or mono- or di-(C1-3-alkyl)-pyrrolyl groups, while the substituents are identical or different, and
    R3 denotes a hydrogen atom,
    a straight-chain or branched C1-6-alkyl group which may be substituted by one to three carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-(C1-3-alkyl)-amino-carbonyl, N-[di-(C1-3-alkyl)-amino-(C1-3-alkyl)]-N-(C1-3-alkyl)-amino-carbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-C1-3-alkyl-aminocarbonyl, heteroaryl-C1-3-alkyl-aminocarbonyl, N-(aryl)-N-(C1-3-alkyl)-aminocarbonyl, N-(heteroaryl)-N-(C1-3-alkyl)-aminocarbonyl, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl, aryl or heteroaryl groups or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group,
    
        while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group may be replaced in position 3 or 4 by an —NH—, —N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,
    
    
    a straight-chain or branched C2-6-alkyl group which is substituted from position 2 onwards by one to three hydroxy, C1-3-alkoxy, aryloxy, heteroaryloxy, amino-C1-3-alkyloxy, C1-3-alkyl-amino-C1-3-alkyloxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, ω-hydroxy-C2-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, heteroaryl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, N—(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-4-alkoxy-carbonyl)-amino, arylcarbonylamino, N—(C1-3-alkyl)-N-(aryl-carbonyl)-amino, (ω-hydroxy-C2-3-alkyl)-amino, di-(ω-hydroxy-C2-3-alkyl)-amino, arylamino, heteroarylamino, C1-3-alkylsulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino, (C1-3-alkyl-amino)-carbonyl-amino, [di-(C1-3-alkyl)-amino]-carbonyl-amino, (C1-3-alkyl-amino)-C1-3-alkyl-carbonyl-amino, [di-(C1-3-alkyl)-amino]-C1-3-alkyl-carbonyl-amino, N-(aryl-C1-13-alkyl-carbonyl)-N—(C1-3-alkyl)-amino, N—(C1-3-alkyl)-N—[(C1-3-alkyl-amino)-carbonyl]-amino or N—(C1-3-alkyl)-N-{[di-(C1-3-alkyl)-amino]-carbonyl}-amino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, arylamino-carbonyl, heteroarylaminocarbonyl-, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl-, aryl or heteroaryl group or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneimino-carbonyl group,
    
        while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,
    
    
    a C2-4-alkenyl or C2-4-alkynyl group, while between the nitrogen atom to which R3 is bound and the multiple bond there is at least one sp3-hybridised carbon atom and the alkenyl or alkynyl group may be substituted by one to three C1-3-alkyl groups,
    a C1-5-alkyl group in the methylene group which is adjacent to the nitrogen atom to which R3 is bound may be replaced by an —NH—, or a —N(C1-3-alkyl)-group or by an oxygen atom,
    a C1-4-alkyloxy group or
    an amino group which may be substituted by one or two C1-3-alkyl, aryl, aryl-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-4-alkyloxy-carbonyl, arylcarbonyl or aryl-C1-3-alkyl-carbonyl groups, while the substituents may be identical or different,
    while the above-mentioned alkyl groups may be straight-chain or branched,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.



Unless otherwise stated, by a heteroaryl group or a heteroaromatic ring is preferably meant a furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl group, which may be mono-, di- or trisubstituted by a fluorine, chlorine, bromine or iodine atom or an amino, nitro, cyano, C1-3-alkyl, C1-3-alkyloxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, or trifluoromethyl group, while the substituents are identical or different, and to which a phenyl ring may be fused via two adjacent atoms.
By an aryl group is meant, unless otherwise stated, a phenyl or naphthyl group; the phenyl group is preferred. Unless otherwise stated, an aryl group of this kind may be substituted by a nitro, cyano, C1-3-alkyloxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group.
Preferred are those compounds of general formula I, wherein

    R2 and R3 are as hereinbefore defined and
    R1 denotes a methyl, ethyl, n-propyl, isopropyl, n-pentyl, trifluoromethyl or phenyl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.



Particularly preferred are those compounds of general formula I, wherein

    R1 denotes a methyl or ethyl group,
    R2 denotes an ethyl, propyl, butyl or pentyl group,
    a pyridinyl, furanyl or pyrazinyl group,
    a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or
    a phenyl group which may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or by one or two C1-3-alkyl, nitro, cyano, amino, C1-3-alkylcarbonylamino, phenylcarbonylamino, C1-3-alkylsulphonylamino, trifluoromethyl, carboxy, C1-3-alkoxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, C1-3-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, hydroxycarbonyl-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkylaminocarbonyl, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, amino-C1-3-alkyl or C1-3-alkyl-carbonylamino-C1-3-alkyl groups, while the substituents are identical or different, and
    R3 denotes a hydrogen atom,
    a straight-chain or branched C1-6-alkyl group which may be substituted by a carboxy, C1-4-alkoxy-carbonyl, phenyl, pyridinyl, indolyl, imidazolyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group,
    
        while the above-mentioned phenyl group may optionally be substituted by nitro, cyano, C1-3-alkyloxy, [di-(C1-3-alkyl)-amino]-C1-3-alkyloxy, an amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group and
        in the above-mentioned cycloalkyleneimino and cycloalkyleneiminocarbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,
    
    
    a straight-chain or branched C2-6-alkyl group which is substituted from position 2 onwards by a hydroxy, C1-3-alkoxy, ω-hydroxy-C2-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-4-alkoxy-carbonyl)-amino, phenylcarbonylamino, N—(C1-3-alkyl)-N-(phenylcarbonyl)-amino, di-(ω-hydroxy-C2-3-alkyl)-amino, pyridinylamino, nitro-pyridinyl-amino, chloro-trifluoromethyl-pyridinylamino, C1-3-alkylsulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino or C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C1-4-alkoxy-carbonyl, phenyl, pyridinyl, imidazolyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group,
    
        while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 may be replaced by a carbonyl group,
        and the above-mentioned phenyl groups may optionally be substituted by an amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group, or
    
    
    or represent a propenyl or propynyl group,
    but particularly those compounds wherein
    R1 denotes a methyl group,
    R2 denotes an ethyl, propyl, butyl or pentyl group,
    a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or
    a phenyl group which may be substituted by one or two fluorine, chlorine or bromine atoms or by one or two trifluoromethyl, nitro, cyano, C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, amino-C1-3-alkyl or C1-3-alkyl-carbonylamino-C1-3-alkyl-groups, while the substituents are identical or different, and
    R3 denotes a straight-chain or branched C1-5-alkyl group which may be substituted by a carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(2-hydroxy-ethyl)-aminocarbonyl, piperazinylcarbonyl, 4-(C1-3-alkyl)-piperazinyl-carbonyl, 4-(C1-4-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group,
    
        while the phenyl group may optionally be substituted by a nitro, cyano, C1-3-alkyloxy, [di-(C1-3-alkyl)-amino]-C1-3-alkyloxy, amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group,
    
    
    a C2-5-alkyl group which is terminally substituted by a hydroxy, C1-3-alkoxy, phenyloxy, 2-hydroxy-ethoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkoxy-carbonyl)-amino, phenylcarbonylamino, N—(C1-3-alkyl)-N-(phenylcarbonyl)-amino, pyridinylamino, nitro-pyridinyl-amino, di-(2-hydroxy-ethyl)-amino, 3-chloro-5-trifluoromethyl-pyridin-2-yl-amino, C1-3-alkylsulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino, indolyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, morpholinyl, piperazinyl or 4-(C1-3-alkyl)-piperazinyl group and may optionally additionally be substituted from position 1 onwards by a carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(2-hydroxy-ethyl)-amino-carbonyl, piperazinylcarbonyl, 4-(C1-3-alkyl)-piperazinyl-carbonyl, 4-(C1-4-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group, or
    an amino group which may be substituted by one or two C1-3-alkyl, aryl, aryl-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-4-alkyloxy-carbonyl, arylcarbonyl or aryl-C1-3-alkyl-carbonyl groups, while the substituents may be identical or different,
    while the above-mentioned alkyl groups may be straight-chain or branched,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.



Most particularly preferred are those compounds of general formula I, wherein

    R1 denotes a methyl group,
    R2 denotes an ethyl, propyl, butyl or pentyl group,
    a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy or ethylenedioxy group, or
    a phenyl group and
    R3 denotes a C1-4-alkyl group which may be terminally substituted by a C1-4-alkoxy-carbonyl group, or
    a C2-4-alkyl group which is terminally substituted by a C1-3-alkyl-carbonylamino, phenylcarbonylamino, di-(C1-3-alkyl)-amino, phenyl, pyridinyl or C1-3-alkylsulphonylamino group,
    while the above-mentioned alkyl groups may be straight-chain or branched,
    the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof;
    the following compounds of general formula I deserve particular mention:
    (a) 5-acetyl-3-[3-(methoxycarbonylpropylamino)-(benzo-[1,3]dioxol-5-yl)-methylidene]-2-indolinone






    (b) 5-acetyl-3-[isopropylamino-phenyl-methylidene]-2-indolinone






    (c) 5-acetyl-3-[propylamino-phenyl-methylidene]-2-indolinone






    (d) 5-acetyl-3-[(3-methoxycarbonyl-propylamino)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methylidene]-2-indolinone






    (e) 5-acetyl-3-[(benzo[1,3]dioxol-5-yl)-(3-(benzoylamino-propylamino)-methylidene]-2-indolinone






    (f) 5-acetyl-3-[(benzo[1,3]dioxol-5-yl)-(3-(butyrylamino-propylamino)-methylidene]-2-indolinone






    (g) 5-acetyl-3-[(3-methanesulphonylamino-propylamino)-phenyl-methylidene]-2-indolinone






    (h) 5-acetyl-3-[1-(3,4-difluorophenyl)-1-(N′,N′-dimethylhydrazino)-methylidene]-2-indolinone






    (i) 5-acetyl-3-[1-(4-dimethylamino-butyl)-butenylidene]-2-indolinone






    (j) 5-acetyl-3-[1-phenyl-1-(3-pyridin-3-yl-propylamino)-methylidene]-2-indolinone






as well as the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

    a) reacting a compound of general formula






wherein R1 and R2 are as hereinbefore defined,

    R18 denotes a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
    Z denotes a leaving group such as e.g. a halogen atom, a hydroxy, alkoxy, alkyl-sulphonyl, trialkylsilyloxy-, alkyl-arylsulphonyl, or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy, methanesulphonyl, trimethylsilyloxy, toluene-sulphonyl or benzyloxy group,
    with an amine of general formula

R3—NH2  (III),

    wherein R3 is as hereinbefore defined,

while any hydroxy, amino or imino groups optionally contained in the groups R2 and/or R3 may be temporarily protected by suitable protective groups.



A suitable protective group for the nitrogen atom of the lactam group may be for example an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group.
The reaction is expediently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate, at temperatures between 20 and 175° C., while any protective group used may simultaneously be cleaved as a result of transamidation.
If Z in a compound of general formula II denotes a halogen atom, then the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120° C.
If Z in a compound of general formula II denotes a hydroxy, alkoxy or arylalkoxy group, then the reaction is preferably carried out at temperatures between 20 and 200° C.
If any protecting group used subsequently has to be cleaved, this is conveniently carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.,

    or advantageously by transamidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
    b) in order to prepare a compound of formula I which contains an aminocarbonyl group:
    reacting a compound which contains a carboxy group with the corresponding amine to obtain the corresponding aminocarbonyl compound;
    c) in order to prepare a compound of formula I which contains a carbonylamino group:
    reacting a compound which contains an amino group with the corresponding acid chloride to obtain the corresponding carbonylamino compound;
    d) in order to prepare a compound of formula I which contains an aminomethyl group: hydrogenating a compound which contains a cyano group to obtain the corresponding aminomethyl derivative;
    e) in order to prepare a compound of formula I which contains an amino group:

reducing a compound which contains a nitro group.



Then any protective groups optionally used during the reaction may be cleaved and/or

    the compounds of general formula I thus obtained may be resolved into their enantiomers and/or diastereomers and/or

the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids or bases.



Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to III used as starting materials are either known from the literature or may be obtained by methods known from the literature (cf. Examples I to VIII).
As already mentioned hereinbefore, the compounds according to the invention of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on the enzyme GSK-3.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which exists in two isoforms, GSK-3α and GSK-3β. GSK-3 phosphorylates and inactivates not only glycogen synthase, a key enzyme of the insulin-dependent regulation of glycogen synthesis (Embi et al., Eur. J. Biochem. 107, 519-527, (1980)), but also a number of other regulatory proteins in vitro. These proteins include the microtubule associated protein Tau, elongation initiation factor 2b (eIF2b), β-catenin, axin, ATP-citratelyase, heat-shock-factor 1, c-jun, c-myc, c-myb, CREB and CEBPα. These different substrates imply a role for GSK-3 in numerous fields of cell metabolism, proliferation, differentiation and development.
Type 2 diabetes is characterised by insulin resistance in various tissues such as skeletal muscle, liver and fatty tissue and by altered secretion of insulin from the pancreas. The storage of glycogen in liver and muscle is of great importance for maintaining the glucose equilibrium. In type 2 diabetes the activity of glycogen synthase is reduced and thus the rate of glycogen synthesis is reduced. It has also been shown that GSK-3 is expressed to a greater extent in type 2 diabetic muscle and hence a reduced GSK-3 activity is associated with a reduced rate of glycogen synthesis (Nikoulina et al., diabetes 49, 263-271, (2000)). Inhibition of the GSK-3 activity stimulates glycogen synthase, thus intensifies glycogen synthesis and leads eventually to a reduction in the glucose levels. GSK-3 inhibition is therefore of therapeutic relevance for the treatment of type 1 and type 2 diabetes and also diabetic neuropathy.
Alzheimer's disease is characterised in that the microtubule-associated protein Tau is present in excessively strongly phosphorylated form (Cohen & Frame, Nature Reviews: Molecular Cell Biology, 2, 1-8, (2001)). GSK-3 phosphorylates many of these phosphorylations sites of Tau in vitro, thereby preventing binding to microtubules. As a result, Tau is available for increased filament assembly, which is at the root of Alzheimer's disease and other neurological diseases of neuronal degeneration. It has been shown that GSK-3 inhibitors such as insulin or lithium bring about partial dephosphorylation of Tau in neuronal cells (Cross et al., J. Neurochem. 77, 94-102 (2001)). GSK-3 inhibition may therefore be of therapeutic relevance for the treatment of degenerative neurological diseases such as Alzheimer's disease.
Inhibitors of GSK-3 activity may thus be of therapeutical and/or preventive benefit for a number of diseases where it is useful to inhibit GSK-3, such as diabetes and diabetes-associated diseases, chronic neurodegenerative diseases and dementias, such as Alzheimer's disease, Parkinson's syndrome, Pick's disease, dementia in subcortical arteriosclerotic encephalopathy (SAE), Huntington's chorea, multiple sclerosis, infectious diseases (meningoencephalitis, syphilis, brain abscess, Creutzfeldt-Jakob disease, AIDS), dementia complex with Lewy bodies, neurotraumatic diseases such as acute stroke, schizophrenia, manic depression, brain haemorrhage, alopecia, obesity, atherosclerotic cardiovaskular diseases, high blood pressure, PCO syndrome, metabolic syndrome, ischaemia, cancer, leukopenia, Down's syndrome, inflammations, immunodeficiency.
A new study (Sato, N. et al., Nature Medicine 10, 55-63 (2004)) shows that GSK-3 inhibitors may acquire the pluripotence of stem cells, which may open up new possibilities in the field of regenerative therapies using stem cells.
Determining the GSK-3 Activity
The effect of substances on the GSK-3 activity was carried out according to the following test method, based on the phosphorylation of a 26mer peptide (YRRMVPPSPSLSRHSSFHQpSEDEEE) from glycogen synthase, the sequence of which contains the phosphorylation sites for GSK-3 and the prephosphorylation of which is indicated by (pS).
The test substance is dissolved in DMSO/water. GSK3β (University of Dundee, UK) dissolved in 10 mM MOPS (morpholinopropanesulphonic acid), 0.05 mM EDTA, 0.005% Brij, 2.5% glycerol, 0.05% mercaptoethanol, pH 7.0, is combined with 10 μM [33P]-ATP, 0.25 μM of 26mer peptide and incubated with the dissolved substance in 50 mM tris, 10 mM MgCl2, 0.1% mercaptoethanol, pH 7.5, at ambient temperature. The reaction was stopped by the addition of 75 mM phosphoric acid. The reaction mixture was transferred onto Phosphocellulose filter plates (Millipore) and filtered to dryness and washed twice with 75 mM phosphoric acid. The phosphorylation was determined by measuring the radioactivity on the filter in a scintillation counter (Topcount, Packard). The ability of a substance to inhibit GSK-3 is determined by comparing the signal of a reaction mixture containing various concentrations of the substance with the signal of the reaction mixture without any substance. The IC50 values are calculated by non-linear regression analysis using GraphPad Prism software.
Typical IC50 values for the substances investigated were between 0.0001 μM and 1 μM.
Determining Glycogen Synthesis
This test serves to investigate the effect of test substances on glycogen synthesis in cells.
C3A hepatoma cells (ATCC) are seeded at a density of 100000 cells/ml in 96-well plates and grown to confluence as a monolayer in the medium. The medium is removed and the cells are washed several times with PBS and then incubated in KRBH buffer (134 mM NaCl, 3.5 mM KCl, 1.2 mM KH2PO4, 0.5 mM MgSO4, 1.5 mM CaCl2, 5 mM NaHCO3, 10 mM HEPES, pH 7.4) with 0.1% BSA and 0.5 mM glucose for 60 min at 37° C. Test substance and 0.2 μCi D-[U14C]glucose (Amersham) are added and the cells are incubated for a further 60 min under the same conditions. After the removal of the incubation buffer the cells are washed several times with cold PBS and then lysed for 10 min at 37° C. and 10 min at ambient temperature with 1 M NaOH. The cell lysates are transferred onto filter plates and the glycogen is precipitated by incubating for 2 h with cold ethanol (70%) on ice. The precipitates are washed several times with ethanol and filtered to dryness. The glycogen synthesised is determined by measuring the radioactivity (14C-glucose incorporated) on the filter plates in a scintillation counter (Topcount, Packard).
The ability of a substance to stimulate glycogen synthesis is determined by comparing the signal of a reaction mixture containing various concentrations of the substance with the signal of the reaction mixture without any substance.
Oral Glucose Tolerance Test
Fasted db/db mice 7 to 9 weeks old (Janvier, France) are weighed and blood is taken from the tip of the tail. This blood is used for the first measurement of glucose on the basis of which the animals are randomised and divided into groups. The test substance to be tested may be given either orally or i.p. as a suspension in 0.5% Natrosol. 30 minutes after the administration of the substance the animals are given orally 2 g/kg glucose in a volume of 0.1 ml/100 g body weight dissolved in NaCl solution. Subsequently, the glucose values are determined from the tail blood using a glucometer (Ultra OneTouch, Lifescan) at specific time intervals [30, 60, 120 and 180 minutes after oral administration of the glucose].
For example, compound 1.009 exhibits a significant activity in the oral glucose tolerance test.
The compounds prepared according to the invention are well tolerated as, for example, after oral administration of 10 mg/kg of the compound of Example 1.009 to mice no changes were observed in the animals' behaviour.
The compounds according to the invention may also be used in combination with other active substances. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPP-IV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. The list also includes SGLT2-inhibitors such as T-1095, inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
In addition, combinations with drugs for influencing high blood pressure such as e.g. A-II antagonists or ACE inhibitors, diuretics, β-blockers, Ca-antagonists and others or combinations thereof are suitable.
Generally speaking, GSK-3 inhibitors may be administered in various ways: by oral, transdermal, intranasal or parenteral route or, in special cases, by intrarectal route. The preferred method of administration is by oral route daily, possibly several times a day. GSK-3 inhibitors are effective over wide dosage range. Thus, the dosage may be between 0.001 and 100 mg/kg, for example.
For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples that follow are intended to illustrate the invention:
Preparation of the Starting Compounds:


EXAMPLE I
5-acetyl-2-indolinone




171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath. Then 78 g (1,1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is maintained at 10-12° C. The reaction mixture is left overnight to come up slowly to ambient temperature. Then the solution is slowly added to 1 kg ice with vigorous stirring. The slurry is diluted with 1 l water and stirred for another 30 min. Then the precipitate is suction filtered.
Yield: 80.9 g (86.3% of theory)
Rf=0.36 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
C10H9NO2 (MW=175.19)
Mass spectrum: m/z=174 (M−H)−
The following compounds are prepared analogously to Example I:
(1) 5-propiony1-2-indolinone
Prepared from 2-indolinone and propionyl chloride
Yield: 72% of theory
Rf=0.44 (silica gel, methylene chloride/methanol 9:1)
C11H11NO2(MW=189.22)
Mass spectrum: m/z=188 (M−H)−
(2) 5-butyryl-2-indolinone
Prepared from 2-indolinone and butyric acid chloride (butyrylchloride)
Yield: 68% of theory
C12H13NO2 (MW=203.24)
Mass spectrum: m/z=202 (M−H)−
(3) 5-isobutyryl-2-indolinone
Prepared from 2-indolinone and isobutyrylchloride
Yield: 13% of theory
C12H13NO2 (MW=203.24)
Mass spectrum: m/z=202 (M−H)−
(4) 5-hexanoyl-2-indolinone
Prepared from 2-indolinone and hexanoic acid chloride
Yield: 88% of theory
Rf=0.51 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
C14H17NO2 (MW=231.30)
Mass spectrum: m/z=230 (M−H)−
(5) 5-benzoyl-2-indolinone
Prepared from 2-indolinone and benzoic acid chloride
Yield: 80% of theory
Rf=0.46 (silica gel, methylene chloride/methanol 9:1)
C15H11NO2 (MW=237.26)
Mass spectrum: m/z=236 (M−H)−
EXAMPLE II
1,5-diacetyl-2-indolinone




48.9 g (0.279 mol) 5-acetyl-2-indolinone are stirred in 400 ml acetic anhydride in an oil bath at 140° C. for 2 h. The starting material dissolves during this time.
Then the reaction mixture is left to cool, evaporated down, the precipitate is removed by suction filtering, washed with ether and the product is dried.
Yield: 56.0 g (92.4% of theory)
Rf=0.41 (silica gel, methylene chloride/methanol 50:1)
C12H11NO3 (MW=217.223)
Mass spectrum: m/z=216 (M−H)−
The following compounds are prepared analogously to Example II:
(1) 1-acetyl-5-propionyl-2-indolinone
Prepared from 5-propionyl-2-indolinone and acetic anhydride
Yield: 79% of theory
Rf=0,68 (silica gel, methylene chloride/methanol 9:1)
C13H13NO3 (MW=231.25)
Mass spectrum: m/z=232 (M+H)+
(2) 1-acetyl-5-benzoyl-2-indolinone
Prepared from 5-benzoyl-2-indolinone and acetic anhydride
Yield: 89% of theory
Rf=0,60 (silica gel, methylene chloride/methanol 30:1)
C17H13NO3 (MW=279.294)
Mass spectrum: m/z=278 (M−H)−
(3) 1-acetyl-5-hexanoyl-2-indolinone
Prepared from 5-hexanoyl-2-indolinone and acetic anhydride
Rf=0,74 (silica gel, methylene chloride/methanol 30:1)
C16H19NO3 (MW=273.33)
Mass spectrum: m/z=272 (M−H)−
EXAMPLE III
1,5-diacetyl-3-(ethoxy-phenyl-methylidene)-2-indolinone




32.6 g (150 mmol) 1,5-diacetyl-2-indolinone are suspended in 100 ml triethyl orthobenzoate and stirred overnight at 110° C. with 150 ml acetic anhydride. Then another 50 ml triethyl orthobenzoate are added and the mixture is stirred for another 24 h. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.
Yield: 38 g (72.5% of theory)
Rf=0.60 (silica gel, methylene chloride/methanol 30:1)
C21H19NO4 (MW=349.384)
Mass spectrum: m/z=350 (M+H)+
The following compounds are prepared analogously to Example III:
(1) 1-acetyl-5-hexanoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone
Prepared from 1-acetyl-5-hexanoyl-2-indolinone and triethyl orthobenzoate
Yield: 29% of theory
Rf=0,72 (silica gel, methylene chloride/methanol 30:1)
C25H27NO4 (MW=405.491)
Mass spectrum: m/z=428 (M+Na)+
(2) 1-acetyl-5-benzoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone
Prepared from 1-acetyl-5-benzoyl-2-indolinone and triethyl orthobenzoate
Yield: 65% of theory
Rf=0,72 (silica gel, methylene chloride/methanol 30:1)
C26H21NO4 (MW=411.455)
Mass spectrum: m/z=412 (M+H)+
(3) 1,5-diacetyl-3-(1-methoxy-propylidene)-2-indolinone
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthopropionate
Yield: 80% of theory
Rf=0.50 (silica gel, methylene chloride/methanol 50:1)
C16H17NO4 (MW=287.311)
Mass spectrum: m/z=288 (M+H)+
(4) 1,5-diacetyl-3-(1-methoxy-butylidene)-2-indolinone
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthobutyrate
Yield: 71% of theory
Rf=0.53 (silica gel, methylene chloride/methanol 50:1)
C17H19NO4 (MW=301.337)
Mass spectrum: m/z=302 (M+H)+
(5) 1,5-diacetyl-3-(1-methoxy-pentylidene)-2-indolinone
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthovalerate
Yield: 66% of theory
Rf=0.60 (silica gel, methylene chloride/methanol 50:1)
C18H21NO4 (MW=315.364)
Mass spectrum: m/z=316 (M+H)+
(6) 1,5-diacetyl-3-(1-methoxy-2-methyl-propylidene)-2-indolinone
Prepared from 1,5-diacetyl-2-indolinone and 1,1,1-trimethoxy-2-methylpropane
Yield: 40% of theory
Rf=0.71 (silica gel, ethyl acetate:cyclohexane:methanol 9:9:2)
C17H19NO4 (MW=301.337)
Mass spectrum: m/z=302 (M+H)+
(7) 1,acetyl-5-propionyl-3-(1-methoxy-propylidene)-2-indolinone
Prepared from 1-acetyl-5-propionyl-2-indolinone and trimethyl orthopropionate
(8) 1,acetyl-5-hexanonyl-3-(1-methoxy-propylidene)-2-indolinone
Prepared from 1-acetyl-5-hexanoyl-2-indolinone and trimethyl orthopropionate
EXAMPLE IV
1-acetyl-5-butyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone




10 g (49 mmol) 5-butyryl-2-indolinone (Ex. 1.2) are stirred in 200 ml acetic anhydride for 5 h at 130° C. Then 35 ml triethyl orthobenzoate are added and the mixture is stirred for a further 4 h at 100° C. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.
Yield: 11.5 g (62% of theory)
Rf=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
C23H23NO4 (MW=377.438)
Mass spectrum: m/z=378 (M+H)+
The following compounds are prepared analogously to Example IV:
(1) 1-acetyl-5-isobutyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone
Prepared from 5-isobutyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate
Rf=0.55 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
(2) 1,5-diacetyl-3-[1-methoxy-ethylidene]-2-indolinone




Prepared from 5-acetyl-2-indolinone, acetic anhydride and trimethyl orthoacetate
Rf=0.40 (silica gel, methylene chloride/methanol 50:1)
(3) 1-acetyl-5-propionyl-3-(ethoxy-phenyl-methylidene)-2-indolinone




Prepared from 5-propionyl-2-indolinone, acetic anhydride and triethyl orthobenzoate
Rf=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
(4) 1-acetyl-5-hexanoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone




Prepared from 5-hexanoyl-2-indolinone, acetic anhydride and triethyl orthobenzoate
Rf=0.72 (methylene chloride/methanol 30:1)
(5) 1-acetyl-5-butyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone




Prepared from 5-butyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate
Rf=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
EXAMPLE V
1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone




4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are stirred overnight together with 4 g 3,4-dimethoxybenzoic acid, 7.1 g TBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) and 14 ml triethylamine in 80 ml DMF (dimethylformamide) at ambient temperature. Then the mixture is poured onto 300 ml ice water with 10 ml of conc. hydrochloric acid and the precipitate formed is suction filtered. The residue is washed with a little methanol and then with ether.
Yield: 6.2 g (81.3% of theory)
Rf=0.85 (silica gel, methylene chloride/methanol 9:1)
C21H19NO6 (MW=381.382)
Mass spectrum: m/z=381 (M)+
The following compounds are prepared analogously to Example V:
(1) 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and piperonylic acid (benzo[1,3]dioxole-5-carboxylic acid)
Yield: 60% of theory
Rf=0.70 (silica gel, methylene chloride/methanol 9:1)
C20H15NO6 (MW=365.339)
Mass spectrum: m/z=366 (M+H)+
(2) 1,5-diacetyl-3-[(4-nitro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-nitrobenzoic acid
Yield: 82% of theory
Rf=0.38 (silica gel, methylene chloride/methanol 9:1)
C19H14N2O6 (MW=366.328)
Mass spectrum: m/z=367 (M+H)+
(3) 1,5-diacetyl-3-[(3-nitro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3-nitrobenzoic acid
Yield: 75% of theory
Rf=0.38 (silica gel, methylene chloride/methanol 9:1)
C19H14N2O6 (MW=366.328)
Mass spectrum: m/z=367 (M+H)+
(4) 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and monomethyl terephthalate
Yield: 71% of theory
Rf=0.41 (silica gel, methylene chloride/methanol 30:1)
C21H17NO6 (MW=379.366)
Mass spectrum: m/z=380 (M+H)+
(5) 1,5-diacetyl-3-[(4-chloro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-chlorobenzoic acid
Yield: 87% of theory
C19H14ClNO4 (MW=355.776)
Mass spectrum: m/z=356/358 (M+H)+
(6) 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3,4-dichlorobenzoic acid
Yield: 83% of theory
C19H13Cl2NO4 (MW=390.221)
Mass spectrum: m/z=390/392/394 (M+H)+
(7) 1,5-diacetyl-3-[(4-cyano-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-cyanobenzoic acid
Yield: 71% of theory
Rf=0.32 (silica gel, methylene chloride/methanol 9:1)
C20H14N2O4 (MW=346.341)
Mass spectrum: m/z=347 (M+H)+
(8) 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-trifluoromethyl-benzoic acid
Yield: 83% of theory
C20H14F3NO4 (MW=389.328)
Mass spectrum: m/z=390 (M+H)+
(9) 1,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 2,3-dihydro-1.4-benzodioxine-6-carboxylic acid
Yield: 90% of theory
Rf=0.75 (silica gel, methylene chloride/methanol 9:1)
C21H17NO6 (MW=379.366)
Mass spectrum: m/z=380 (M+H)+
(10) 1,5-diacetyl-3-[(3-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3-methoxybenzoic acid
Yield: 70% of theory
Rf=0.67 (silica gel, methylene chloride/methanol 9:1)
(11) 1,5-diacetyl-3-[(4-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-methoxybenzoic acid
Yield: 59% of theory
Rf=0.39 (silica gel, methylene chloride/methanol 9:1)
C20H17NO5 (MW=351.356)
Mass spectrum: m/z=350 (M−H)−
(12) 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1-acetyl-5-propionyl-2-indolinone and piperonylic acid (benzo[1,3]-dioxole-5-carboxylic acid)
Yield: 67% of theory
Rf=0.49 (silica gel, methylene chloride/methanol 30:1)
C21H17NO6 (MW=379.366)
Mass spectrum: m/z=380 (M+H)+
(13) 1,5-diacetyl-3-[(4-bromophenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-bromobenzoic acid
Yield: 89% of theory
C19H14BrNO4 (MW=400.227)
Mass spectrum: m/z=400/402 (M+H)+
(14) 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3,5-dichlorobenzoic acid
Yield: 79% of theory
Rf=0.26 (silica gel, methylene chloride/methanol 30:1)
C19H13Cl2NO4 (MW=390.221)
Mass spectrum: m/z=390/392/394 (M+H)+
(15) 1,5-diacetyl-3-[(3,5-dimethoxyphenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3,5-dimethoxybenzoic acid
Yield: 83% of theory
Rf=0.37 (silica gel, methylene chloride/methanol 30:1)
C21H19NO6 (MW=381.382)
Mass spectrum: m/z=382 (M+H)+
(16) 1,5-diacetyl-3-[(2-chloro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 2-chlorobenzoic acid
Yield: 96% of theory
C19H14ClNO4 (MW=355.776)
Mass spectrum: m/z=356/358 (M+H)+
(17) 1,5-diacetyl-3-[(2-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 2-methoxybenzoic acid
Yield: 27% of theory
C20H17NO5 (MW=351.356)
Mass spectrum: m/z=352 (M+H)+
(18) 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 2,6-difluorobenzoic acid
Yield: 52% of theory
C19H13F2NO4 (MW=357.311)
Mass spectrum: m/z=358 (M+H)+
(19) 1,5-diacetyl-3-[(4-fluorophenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-fluorobenzoic acid
Yield: 77% of theory C19H14FNO4 (MW=339.321)
Mass spectrum: m/z=338 (M−H)−
(20) 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3,4-difluorobenzoic acid
Yield: 91% of theory
(21) 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 2,2-difluoro-benzo[1,3]dioxol-5-carboxylic acid
Yield: 69% of theory
C20H13F2NO6 (MW=401.32)
Mass spectrum: m/z=402 (M+H)+
(22) 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-(2-methoxycarbonyl-ethyl)-benzoic acid
Yield: 23% of theory
C23H21NO6 (MW=407.42)
Mass spectrum: m/z=408 (M+H)+
(23) 1,5-diacetyl-3-[(pyrazin-2-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and pyrazine-2-carboxylic acid
Yield: 57% of theory
C17H13N3O4 (MW=323.311)
Mass spectrum: m/z=324 (M+H)+
(24) 1,5-diacetyl-3-[(pyridin-4-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and isonicotinic acid (pyridine-4-carboxylic acid)
Yield: 87% of theory
C18H14N2O4 (MW=322.323)
Mass spectrum: m/z=323 (M+H)+
(25) 1,5-diacetyl-3-[(furan-3-yl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and furan-3-carboxylic acid
Yield: 73% of theory
C17H13NO5 (MW=311.297)
Mass spectrum: m/z=312 (M+H)+
(26) 1,5-diacetyl-3-[(4-diethylaminomethyl-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-diethylaminomethyl-benzoic acid
Yield: 10% of theory
C24H26N2O4 (MW=406.486)
Mass spectrum: m/z=407 (M+H)+
(27) 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-methoxycarbonyl-methoxy-benzoic acid
Yield: 43% of theory
C22H19NO7 (MW=409.39)
Mass spectrum: m/z=410 (M+H)+
(28) 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-methylsulphonyl-benzoic acid
Yield: 25% of theory
C20H17NO6S (MW=399.418)
Mass spectrum: m/z=400 (M+H)+
(29) 1,5-diacetyl-3-[(4-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 4-diethylamino-ethoxy-benzoic acid
Yield: 27% of theory
C25H28N2O5 (MW=436.500)
Mass spectrum: m/z=437 (M+H)+
(30) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid
Yield: 43% of theory
C25H28N2O5 (MW=436.500)
Mass spectrum: m/z=437 (M+H)+
(31) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid
Yield: 43% of theory
C25H28N2O5 (MW=436.500)
Mass spectrum: m/z=437 (M+H)+
(31) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid
Yield: 43% of theory
C25H28N2O5 (MW=436.500)
Mass spectrum: m/z=437 (M+H)+
(32) 1,5-diacetyl-3-(1-hydroxy-heptylidene)-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and heptanoic acid
(33) 1,5-diacetyl-3-(1-hydroxy-hexylidene)-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and hexanoic acid
(34) 1,5-diacetyl-3-(1-hydroxy-3-methyl-butylidene)-2-indolinone




Prepared from 1,5-diacetyl-2-indolinone and isovaleric acid
EXAMPLE VI
1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-methoxy-methylidene]-2-indolinone




4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate and 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then another 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Yield: 1.6 g (37% of theory)
Rf=0.78 (silica gel, methylene chloride/methanol 50:1)
C22H21NO6 (MW=395.409)
Mass spectrum: m/z=396 (M+H)+
The following compounds are prepared analogously to Example VI:
(1) 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.1)
Yield: 85% of theory
Rf=0.55 (silica gel, methylene chloride/methanol 30:1)
C21H17NO6 (MW=379.366)
Mass spectrum: m/z=380 (M+H)+
(2) 1,5-diacetyl-3-[(4-nitro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-nitro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.2)
Yield: 82% of theory
Rf=0.55 (silica gel, methylene chloride/methanol 30:1)
C20H16N2O6 (MW=380.354)
Mass spectrum: m/z=381 (M+H)+
(3) 1,5-diacetyl-3-[(3-nitro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3-nitro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.3)
Yield: 43% of theory
Rf=0.44 (silica gel, methylene chloride/methanol 9:1)
C20H16N2O6 (MW=380.354)
Mass spectrum: m/z=381 (M+H)+
(4) 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.4)
Yield: 52% of theory
Rf=0.56 (silica gel, methylene chloride/methanol 30:1)
C22H19NO6 (MW=393.393)
Mass spectrum: m/z=394 (M+H)+
(5) 1,5-diacetyl-3-[(4-chloro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-chloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.5)
Yield: 65% of theory
C20H16ClNO4 (MW=369.802)
Mass spectrum: m/z=370/372 (M+H)+
(6) 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.6)
Yield: 72% of theory
C20H15Cl2NO4 (MW=404.247)
Mass spectrum: m/z=404/406/408 (M+H)+
(7) 1,5-diacetyl-3-[(4-cyano-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-cyano-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.7)
Yield: 53% of theory
C21H16N2O4 (MW=360.367)
Mass spectrum: m/z=361 (M+H)+
(8) 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.8)
Yield: 37% of theory
C21H16F3NO4 (MW=403.354)
Mass spectrum: m/z=404 (M+H)+
(9) 1,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-methoxy-methylidene]-2-indolinone




Prepared from 11,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.9)
Yield: 52% of theory
Rf=0.82 (silica gel, methylene chloride/methanol 9:1)
C22H19NO6 (MW=393.393)
Mass spectrum: m/z=394 (M+H)+
(10) 1,5-diacetyl-3-[(3-methoxy-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.10)
Yield: 48% of theory
Rf=0.40 (silica gel, methylene chloride/methanol 9:1)
C21H19NO5 (MW=365.383)
Mass spectrum: m/z=366 (M+H)+
(11) 1,5-diacetyl-3-[(4-methoxy-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.11)
Yield: 85% of theory
Rf=0.35 (silica gel, methylene chloride/methanol 30:1)
C21H19NO5 (MW=365.383)
Mass spectrum: m/z=366 (M+H)+
(12) 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone




Prepared from 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.12)
Yield: 98% of theory
Rf=0.63 (silica gel, methylene chloride/methanol 30:1)
C22H19NO6 (MW=393.393)
Mass spectrum: m/z=394 (M+H)+
(13) 1,5-diacetyl-3-[(4-bromophenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-bromophenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.13)
Yield: 48% of theory
(14) 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.14)
Yield: 44% of theory
Rf=0.86 (silica gel, methylene chloride/methanol 30:1)
C19H13Cl2NO4 (MW=390.221)
Mass spectrum: m/z=388/390/392 (Cl2, M+H)+
(15) 1,5-diacetyl-3-[(3,5-dimethoxy-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3,5-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.15)
Yield: 74% of theory
Rf=0.65 (silica gel, methylene chloride/methanol 30:1)
C22H21NO6 (MW=395.409)
Mass spectrum: m/z=396 (M+H)+
(16) 1,5-diacetyl-3-[(2-chloro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(2-chloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.16)
Yield: 54% of theory
C20H16ClNO4 (MW=369.802)
Mass spectrum: m/z=370/372 (M+H)+
(17) 1,5-diacetyl-3-[(2-methoxy-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(2-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.17)
Yield: 56% of theory
C21H19NO5 (MW=365.383)
Mass spectrum: m/z=366 (M+H)+
(18) 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.18)
Yield: 59% of theory
C20H15F2NO4 (MW=3371.337)
Mass spectrum: m/z=372 (M+H)+
(19) 1,5-diacetyl-3-[(4-fluorophenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-fluorophenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.19)
Yield: 88% of theory
C20H16FNO4 (MW=353.347)
Mass spectrum: m/z=354 (M+H)+
(20) 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.20)
Yield: 23% of theory
C20H15F2NO4 (MW=371.334)
Mass spectrum: m/z=372 (M+H)+
(21) 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl idene]-2-indolinone (Ex. V.21)
Yield: 6% of theory
C21H15F2N O6 (MW=415.346)
Mass spectrum: m/z=416 (M+H)+
(22) 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.22)
Yield: 63% of theory
C24H23NO6 (MW=421.447)
Mass spectrum: m/z=422 (M+H)+
(23) 1,5-diacetyl-3-[furan-3-yl-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[furan-3-yl-hydroxy-methylidene]-2-indolinone (Ex. V.25)
Yield: 59% of theory
C18H15NO5 (MW=325.324)
Mass spectrum: m/z=326 (M+H)+
(24) 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-methoxy-methylidene]-2-indolinon




Prepared from 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-hydroxy-methylidene]-2-indolinone
Yield: 24% of theory
C23H21NO7 (MW=423.415)
Mass spectrum: m/z=424 (M+H)+
(25) 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-methoxy-methylidene]-2-indolinone




Prepared from 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.28)
Yield: 20% of theory
C21H19NO6S (MW=413.445)
Mass spectrum: m/z=414 (M+H)+
(26) 1,5-diacetyl-3-(1-methoxy-octylidene)-2-indolinone




Prepared from 1,5-diacetyl-3-(1-hydroxyl-octylidene)-2-indolinone (Ex. VIII)
Yield: 82% of theory
C21H27NO4S (MW=357.443)
Mass spectrum: m/z=358 (M+H)+
(27) 1,5-diacetyl-3-(1-methoxy-heptylidene)-2-indolinone




Prepared from 1,5-diacetyl-3-(1-hydroxy-heptylidene)-2-indolinone (Ex. V.32)
(28) 1,5-diacetyl-3-(1-methoxy-hexylidene)-2-indolinone




Prepared from 1,5-diacetyl-3-(1-hydroxy-hexylidene)-2-indolinone (Ex. V.33)
(29) 1,5-diacetyl-3-(1-methoxy-3-methyl-butylidene)-2-indolinone




Prepared from 1,5-diacetyl-3-(1-hydroxy-3-methyl-butylidene)-2-indolinone (Ex. V.34)
EXAMPLE VII
1,5-diacetyl-3-[chloro-(Pyrazin-2-yl)-methylidene]-2-indolinone




1.2 g (3.7 mmol) 1,5-diacetyl-3-[(pyrazin-2-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.23) are dissolved in 50 ml dioxane and refluxed with 2 ml carbon tetrachloride and 2 g triphenylphosphine for 5 h. Then the mixture is left to cool and evaporated down. The residue is chromatographed through a silica gel column with methylene chloride/methanol 25:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Yield: 400 mg (40% of theory)
Rf=0.70 (silica gel, methylene chloride/methanol 30:1)
C17H12ClN3O3 (MW=341.756)
Mass spectrum: m/z=342/344 (M+H)+ (CL)
The following compound is prepared analogously to Example VII:
(1) 1,5-diacetyl-3-[chloro-(4-(2-dimethylamino-ethoxy)-phenyl)-methylidene]-2-indolinone




EXAMPLE VIII
1,5-diacetyl-3-(1-hydroxy-octylidene)-2-indolinone




4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are dissolved in 20 ml of dimethylformamide and 490 mg dimethylaminopyridine (DMAP) and 6 ml triethylamine added and the mixture is cooled in the ice bath. 3.8 ml (22 mmol) octanoic acid chloride in 20 ml of dimethylformamide are added to this solution and the mixture is stirred for a further 10 min. Then the reaction mixture is added to 150 ml of methylene chloride and 150 ml 1 N hydrochloric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 95:5.
Yield: 740 mg (11% of theory)
C20H25NO4 (MW=343.417)
Mass spectrum: m/z=344 (M)+
Preparation of the End Compounds:

    Eluant:
    A: methylene chloride/methanol 9:1
    B: methylene chloride/methanol 4:1
    C: methylene chloride/methanol/conc. ammonia 9:1:0.1
    D: methylene chloride/methanol 30:1
    E: methylene chloride/methanol/triethylamine 9:1:0.1


In the formulae in the Table the bond drawn free always represents the bond of the relevant group at the point of attachment in the molecule. The entry “—CH3” in the Table thus denotes a methyl group and the entry




denotes an isobutyl group, i.e.—CH2—CH(CH3)2.

EXAMPLE 1
5-acetyl-3-[(3-dimethylamino-propylamino)-phenyl-methylidene]-2-indolinone




0.2 g (0.57 mmol) of 1,5-diacetyl-3-(phenyl-ethoxy-methylidene)-2-indolinone (Ex. III) are suspended in 5 ml of dimethylformamide and stirred with 0.07 ml 3-dimethyl-amino-propylamine at 70° C. for 12 h. Then the mixture is left to cool, 2 ml of methanol and 1 ml 1 N sodium hydroxide solution are added and the mixture is stirred at ambient temperature for 30 min. Then water is added, and the resulting precipitate is filtered off, washed and dried. If necessary, the compound may be purified by chromatography on silica gel. A suitable eluant is methylene chloride/methanol 30:1.
Yield: 0.1 g (82% of theory)
Rf=0.39 (silica gel, methylene chloride/methanol/conc. ammonia 9:1:0.1)
C22H25N3O2 (MW=363.458)
Mass spectrum: m/z=364 (M+H)+
The following compounds of formula I are prepared analogously to Example 1:
















 



















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)





1.001
Me
Ph




III 85.9
(M+H)+ = 350
0.43 (A)


 


1.002
Me
Ph




III 74.1
(M+H)+ = 391
0.51 (A)


 


1.003
Me
Ph




III 88.8
(M+H)+ = 406
0.58 (A)


 


1.004
Me
Ph




III 81.9
(M+H)+ = 379
0.23 (D)


 


1.005
Me
Ph




III 88.5
(M+H)+ = 351
0.22 (D)


 


1.006
Me
Ph




III 80.6
(M+H)+ = 410
0.35 (C)


 


1.007
Me
Ph




III 79.0
(M+H)+ = 376
0.39 (C)


 


1.008
Me
Ph




III 66.4
(M+H)+ = 392
0.27 (C)


 


1.009
Me
Ph




III 64.9
(M+H)+ = 433
0.52 (C)


 


1.010
Me
Ph




III 80.7
(M−H)− = 367
0.42 (A)


 


1.011
Me
Ph




III 54.7
(M−H)− = 382
0.39 (A)


 


1.012
Me
Ph




III 67.1
(M+H)+ = 365
0.48 (A)


 


1.013
Me
Ph




III 32.8
(M+H)+ = 498
0.59 (A)


 


1.014
Me
Ph




III 92.3
(M+H)+ = 379
0.34 (A)


 


1.015
Me
Ph




III 73.1
(M+H)+ = 383
0.33 (A)


 


1.016
Me
Ph




III 57.7
(M+H)+ = 364
0.29 (A)


 


1.017
Me
Ph




III 22.9
(M+H)+ = 444
0.42 (A)


 


1.018
Me








VI.1 53.2
(M+H)+ = 436
0.46 (B)


 


1.019
Me








VI.1 65.2
(M+H)+ = 408
0.43 (A)


 


1.020
Me
Ph




III 11.7
(M+H)+ = 463
0.56 (A)


 


1.021
Me








VI.1 28.7
(M+H)+ = 477
0.31 (A)


 


1.022
Me
Ph




III 66.6
(M+H)+ = 407
0.38 (A)


 


1.023
Me








VI.5 70.2
(M+H)+ = 398/400 (Cl)
0.18 (A)


 


1.024
Me








VI.5 57.0
(M+H)+ = 399/401 (Cl)
0.25 (A)


 


1.025
Me








VI.1 44.9
(M+H)+ = 423
0.32 (A)


 


1.026
Me








VI.6 51.9
(M+H)+ = 447/449/ 451 (Cl2)
0.30 (A)


 


1.027
Me








IV.6 24.5
(M+H)+ = 423/434/ 436 (Cl2)
0.37 (C)


 


1.028
Me








VI.8 35.1
(M+H)+ = 432
0.25 (A)


 


1.029
Me
Ph
Et
III 98
(M+H)+ = 307
0.44 (A)


 


1.030
Me
Ph




III 90.6
(M+H)+ = 317
0.31 (A)


 


1.031
Me
Ph




III 90.3
(M+H)+ = 349
0.48 (A)


 


1.032
Me
Ph
i-Pr
III 77.5
(M+H)+ = 321
0.46 (A)


 


1.033
Me
Ph




III 78.4
(M+H)+ = 335
0.33 (A)


 


1.034
Me
Ph
n-Pr
III 56.7
(M+H)+ = 321
0.31 (A)


 


1.035
Me
Ph




III 93.3
(M+H)+ = 319
0.32 (A)


 


1.036
Me








VI.9 72.1
(M+H)+ = 437
0.38 (A)


 


1.037
Me








VI.8 40.2
(M+H)+ = 447
0.75 (A)


 


1.038
Me








VI.11 76.9
(M+H)+ = 409
0.36 (A)


 


1.039
Me








VI.10 80.3
(M+H)+ = 409
0.36 (A)


 


1.040
Me








VI.13 67.7
(M−H)− = 440/442 (Br)
0.26 (A)


 


1.041
Me
Ph




III 85.0
(M+H)+ = 436
0.28 (A)


 


1.042
Me








VI.14 67.8
(M−H)− = 445/447/ 449 (Cl2)
0.25 (A)


 


1.043
Me








VI.15 71.0
(M+H)+ = 439
0.27 (A)


 


1.044
Me








VI.16 75.5
(M+H)+ = 369/371 (Cl)
0.33 (A)


 


1.045
Me








VI.17 62.2
(M+H)+ = 365
0.05 (CH2Cl2/ MeOH 50:1)


 


1.046
Me








VI.19 68.1
(M+H)+ = 353
0.46 (A)


 


1.047
Me








VI.19 59.4
(M+H)+ = 397
0.45 (A)


 


1.048
Me








VI.20 13.8
(M+H)+ = 371
0.54 (A)


 


1.049
Me








VI.20 51.4
(M+H)+ = 415
0.56 (A)


 


1.050
Me








VI.21 38.5
(M+H)+ = 415
0.31 (A)


 


1.051
Me








VI.21 33.8
(M−H)− = 457
0.46 (A)


 


1.052
Me








VI.21 22.4
(M−H)− = 443
0.37 (B)


 


1.053
Me








VI.7 78.6
(M+H)+ = 404
0.53 (A)


 


1.054
Me








VI.7 90.3
(M+H)+ = 389
0.53 (C)


 


1.055
Me








VI.7 83.8
(M+H)+ = 360
0.36 (A)


 


1.056
Me




n-Pr
VI.7 87.6
(M+H)+ = 345
0.34 (A)


 


1.057
Me








VI.7 86.0
(M+H)+ = 432
0.37 (A)


 


1.058
Me








VI.7 63.4
(M+H)+ = 404
0.49 (A)


 


1.059
Me








VI.7 78.0
(M−H)− = 430
0.33 (A)


 


1.060
Me
Ph
t-Bu
III 68.0
(M+H)+ = 335
0.52 (A)


 


1.061
Me








VI.1 57.0
(M+H)+ = 480
0.44 (A)


 


1.062
Me








VI.7 89.5
(M+H)+ = 403
0.35 (A)


 


1.063
Me








VI.1 63.3
(M+H)+ = 408
0.18 (A)


 


1.064
Me








VI.1 65.7
(M+H)+ = 422
0.38 (A)


 


1.065
Me








VI.1 74.5
(M+H)+ = 431
0.41 (A)


 


1.066
Me








IV.1 67.2
(M+H)+ = 559/561 (Cl)
0.55 (A)


 


1.067
Me








VI.1 57.4
(M+H)+ = 463
0.26 (A)


 


1.068
Me








VI.1 61.0
(M+H)+ = 436
0.36 (A)


 


1.069
Me
Ph




III 61.1
(M+H)+ = 378
0.29 (A)


 


1.070
Me








VI.1 84.8
(M+H)+ = 448
0.42 (A)


 


1.071
Me








VI.1 62.0
(M+H)+ = 484
0.44 (A)


 


1.072
Me








VI.22 58.0
(M+H)+ = 436
0.46 (A)


 


1.073
Me








VI.1 99.9
(M+H)+ = 494
0.46 (A)


 


1.074
Me








VI.1 71.8
(M+H)+ = 450
0.48 (A)


 


1.075
Me








VI.1 65.4
(M+H)+ = 450
0.44 (A)


 


1.076
Me








VI.1 58.1
(M+H)+ = 458
0.55 (A)


 


1.077
Me








VI.22 84.8
(M+H)+ = 464
0.51 (C)


 


1.078
Me








VI.22 68.7
(M+H)+ = 450
0.33 (C)


 


1.079
Me








VI.22 58.8
(M+H)+ = 478
0.31 (C)


 


1.080
Me








VI.1 93.5
(M+H)+ = 508
0.4 (A)


 


1.081
Me








VI.1 76.0
(M+H)+ = 367
0.46 (A)


 


1.082
Me








VI.1 66.6
(M+H)+ = 381
0.44 (A)


 


1.083
Me








VI.1 69.7
(M+H)+ = 411
0.43 (A)


 


1.084
Me








VI.1 55.2
(M+H)+ = 395
0.47 (A)


 


1.085
Me
Ph
H
III 97.0
(M+H)+ = 279
0.39 (C)


 


1.086
Me




H
VI.3 85.1
(M+H)+ = 324
0.53 (C)


 


1.087
Me








VI.12 51.5
(M+H)+ = 437
0.39 (A)


 


1.088
Me








VI.19 66.6
(M+H)+ = 381
0.43 (A)


 


1.089
Me








VI.19 69.1
(M+H)+ = 422
0.09 (A)


 


1.090
Me








VI.19 28.8
(M+H)+ = 484
0.40 (A)


 


1.091
Me








VI.19 92.4
(M+H)+ = 480
0.12 (A)


 


1.092
Me








VI.1 67.0
(M+H)+ = 451
0.45 (A)


 


1.093
Me








VI.1 55.0
(M+H)+ = 451
0.45 (A)


 


1.094
Me








VI.1 72.0
(M+H)+ = 367
0.47 (A)


 


1.095
Me








VI.1 84.0
(M+H)+ = 316
0.41 (A)


 


1.096
Me








VI.1 66.0
(M−H)− = 440
0.53 (A)


 


1.097
Me
Ph




III 60.0
(M−H)− = 396
0.52 (A)


 


1.098
Me
Ph




III 59.0
(M+H)+ = 398
0.60 (C)


 


1.099
Me
Ph




III 85.0
(M+H)+ = 399
0.59 (C)


 


1.100
Me
Ph




III 84.0
(M+H)+ = 422
0.52 (C)


 


1.101
Me
Ph




III 70.0
(M+H)+ = 399
0.25 (C)


 


1.102
Me
Ph




III 73.0
(M+H)+ = 412
0.42 (C)


 


1.103
Me
Ph




III 89.0
(M+H)+ = 384
0.41 (C)


 


1.104
Me
Ph




III 86.0
(M+H)+ = 397
0.58 (C)


 


1.105
Me
Ph




III 81.0
(M+H)+ = 411
0.44 (A)


 


1.106
Me
Ph




III 49.0
(M+H)+ = 411
0.43 (A)


 


1.107
Me
Ph




III 40.0
(M+H)+ = 411
0.41 (A)


 


1.108
Me
Ph




III 73.0
(M+H)+ = 439
0.46 (A)


 


1.109
Me
Ph




III 90.0
(M+H)+ = 425
0.49 (A)


 


1.110
Me
Ph




III 90.0
(M+H)+ = 441
0.40 (A)


 


1.111
Me
Ph




III 93.0
(M+H)+ = 442
0.32 (A)


 


1.112
Me
Ph




III 78.0
(M+H)+ = 335
0.50 (A)


 


1.113
Me
Ph




III 89.0
(M+H)+ = 412
0.50 (C)


 


1.114
Me
Ph




III 87.0
(M+H)+ = 436
n.d.


 


1.115
Me








VI.8 61.0
(M+H)+ = 466
0.35 (A)


 


1.116
Me








VI.8 80.0
(M+H)+ = 465
0.37 (A)


 


1.117
Me








VI.8 77.0
(M+H)+ = 480
0.31 (A)


 


1.118
Me








VI.8 56.0
(M+H)+ = 403
0.50 (A)


 


1.119
Me
Ph




III 80.0
(M+H)+ = 484
0.45 (A)


 


1.120
Me
Ph




III 10.0
(M+H)+ = 436
0.60 (A)


 


1.121
Me
Ph




III 75.0
(M+H)+ = 413
0.43 (A)


 


1.122
Me
Ph




III 30.0
(M+H)+ = 426
0.48 (A)


 


1.123
Me
Ph




III 66.0
(M+H)+ = 427
0.55 (A)


 


1.124
Me








VI.8 54.0
(M+H)+ = 446
0.28 (A)


 


1.125
Me








VI.20 79.0
(M+H)+ = 371
0.21 (A)


 


1.126
Me








VI.20 77.0
(M+H)+ = 385
0.20 (A)


 


1.127
Me
Et




III.3 73.0
(M+H)+ = 349
0.44 (E)


 


1.128
Me
Et




III.3 69.0
(M+H)+ = 387
0.48 (E)


 


1.129
Me
n-Pr




III.4 94.0
(M−H)− = 361
0.47 (A)


 


1.130
Me
n-Pr




III.4 93.0
(M+H)+ = 301
0.51 (A)


 


1.131
Me
n-Pr




III.4 74.0
(M+H)+ = 301
0.63 (A)


 


1.132
Me
n-Pr




III.4 47.0
(M+H)+ = 344
0.31 (C)


 


1.133
Me
n-Pr




III.4 38.0
(M+H)+ = 330
0.62 (C)


 


1.134
Me
n-Pr




III.4 45.0
(M+H)+ = 358
0.51 (C)


 


1.135
Me
n-Bu




III.5 94.0
(M+H)+ = 377
0.54 (E)


 


1.136
Me
n-Bu




III.5 86.0
(M+H)+ = 315
0.69 (E)


 


1.137
Me
n-Bu




III.5 81.0
(M+H)+ = 315
0.69 (E)


 


1.138
Me
n-Bu




III.5 59.0
(M+H)+ = 358
0.22 (A)


 


1.139
Me
n-Bu




III.5 55.0
(M+H)+ = 344
0.22 (A)


 


1.140
Me
n-Bu




III.5 42.0
(M+H)+ = 372
0.12 (A)


 


1.141
Me








VI.1 69.8
(M+H)+ = 465
0.36 (A)


 


1.142
Me








VI.25 68.0
(M+H)+ = 413
0.52 (A)


 


1.143
Me








VI.26 79.6
(M+H)+ = 400
0.08 (A)


 


1.144
Me








VI.26 62.1
(M+H)+ = 357
0.51 (A)


 


1.145
Me








VI.27 76.4
(M+H)+ = 386
0.11 (A)


 


1.146
Me








VI.28 22.0
(M+H)+ = 372
0.23 (C)


 


1.147
Me








VI.29 12.0
(M+H)+ = 358
0.16 (C)


 


1.148
Et
Et




III.7 70.0
(M+H)+ = 344
0.11 (A)


 


1.149
Et
Et




III.7 87.0
(M+H)+ = 363
0.45 (A)


 


1.150
n- C5H11
Et




III.8 73.0
(M+H)+ = 405
0.47 (A)


 


1.151
Me








VI.28 75.0
(M+H)+ = 486
0.27 (C)


 


1.152
Me








VI.28 58.0
(M+H)+ = 391
0.46 (A)


 


1.153
Me








VI.29 37.0
(M+H)+ = 315
0.66 (A)


 


1.154
Me








VI.29 51.0
(M+H)+ = 372
0.24 (A)


 


1.155
Me








VI.29 50.0
(M+H)+ = 377
0.47 (C)









EXAMPLE 2
5-acetyl-3-[benzo[3]dioxol-5-yl-(3-methylamino-propylamino)-methylidene]-2-indolinone




680 mg (1.38 mmol) 5-acetyl-3-[benzo[1.3]dioxol-5-yl-(3-(N-tert-butoxycarbonyl-N-methyl-amino)-propylamino)-methylidene]-2-indolinone (Example 1.073) are added batchwise to a solution of 2 ml trifluoroacetic acid in 20 ml methylene chloride and stirred for 5 h at ambient temperature. Then the mixture is evaporated down, the residue is taken up in methylene chloride, made alkaline with 1 N sodium hydroxide solution and then the organic phase is separated off, dried over sodium sulphate and evaporated down.
Yield: 210 mg (38% of theory)
Rf=0.05 (silica gel, methylene chloride/methanol 9:1)
C22H23N3O4 (MW=393.441)
Mass spectrum: m/z=394 (M+H)+
The following compounds of formula I are prepared analogously to Example 2:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







2.001
Me
Ph




1.013 65.1
(M+H)+ = 398
0.14 (B)


 


2.002
Me
Ph




4.014 52.9
(M+H)+ = 433
0.48 (C)


 


2.003
Me
Ph




4.016 56.7
(M+H)+ = 419
0.38 (C)


 


2.004
Me
Ph




1.041 53.2
(M+H)+ = 336
0.40 (C)


 


2.005
Me








1.061 97.3
(M+H)+ = 380
0.08 (A)


 


2.006
Me








1.080 81.1
(M+H)+ = 408
0.1 (A)


 


2.007
Me
Ph




1.114 82.0
(M+H)+ = 336
0.32 (C)









EXAMPLE 3
5-acetyl-3-[(carboxymethyl-amino)-phenyl-methylidene]-2-indolinone




88 mg (0.25 mmol) 5-acetyl-3-[(methoxycarboxymethyl-amino)-phenyl-methylidene]-2-indolinone (Example 1.005) are suspended in 0.5 ml 1 N sodium hydroxide solution and 5 ml of methanol and refluxed for 4 h. Then the mixture is cooled, 0.5 ml 1 N hydrochloric acid are added and the precipitate is removed by suction filtering.
Yield: 81 mg (95% of theory)
C19H6N2O4 (MW=336.345)
Mass spectrum: m/z=337 (M+H)+
The following compounds of formula I are prepared analogously to Example 3:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







3.001
Me
Ph




1.004 91.3
(M+H)+ = 351
not determined


 


3.002
Me
Ph




1.014 34.6
(M+H)+ = 365
0.19 (A)


 


3.003
Me
Ph




1.012 88.5
(M−H)− = 349
0.47 (A + glacial acetic acid)


 


3.004
Me
Ph




1.022 57.0
(M+H)+ = 393
0.26 (A)


 


3.005
Me








1.022 85.5
(M+H)+ = 409
0.31 (A)


 


3.006
Me








1.026 42.5
(M−H)− = 431/433/ 435 (Cl2)
0.31 (A)


 


3.007
Me








1.036 82.7
(M−H)− = 421
0.33 (A)


 


3.008
Me








1.037 41.3
(M−H)− = 431
0.22 (A)


 


3.009
Et








1.087 82.6
(M+H)+ = 423
0.78 (B)


 


3.010
Me








1.038 93.1
(M−H)− = 393
0.7 (B)


 


3.011
Me








1.039 79.2
(M−H)− = 393
0.33 (A)


 


3.012
Me








1.042 90.9
(M+H)+ = 433/435/ 437 (Cl2)
0.32 (A)


 


3.013
Me








1.043 77.5
(M+H)+ = 425
0.27 (A)


 


3.014
Me








1.047 79.4
(M+H)+ = 383
0.38 (A)


 


3.015
Me








1.049 78.4
(M+H)+ = 401
0.36 (A)


 


3.016
Me








7.004 19.5
(M+H)+ = 394
0.09 (A + glacial acetic acid)


 


3.017
Me








7.012 95.5
(M+H)+ = 380
0.05 (A + glacial acetic acid)


 


3.018
Me








7.010 56.3
(M+H)+ = 442
0.02 (C)


 


3.019
Me








6.006 98
(M+H)+ = 436
0.39 (A + glacial acetic acid)


 


3.020
Me








1.072 82.5
(M+H)+ = 442
0.45 (MeOH)


 


3.021
Me








5.014 93.4
(M+H)+ = 408
0.39 (MeOH)


 


3.022
Me








1.077 85.9
(M+H)+ = 450
0.24 (MeOH)


 


3.023
Me








1.078 72.4
(M+H)+ = 436
0.22 (MeOH)


 


3.024
Me








1.079 57.4
(M−H)− = 462
0.15 (MeOH)


 


3.025
Me








8.004 89.0
(M+H)+ = 450
0.56 (A)









EXAMPLE 4
5-acetyl-3-{[3-(N,N-bis-(2-hydroxyethyl)-carbamoyl)-propylamino]-phenyl-methylene}-2-indolinone




100 mg (0.27 mmol) 5-acetyl-3-[3-(carboxy-propylamino)-phenyl-methylidene]-2-indolinone (Ex. 3.002) are stirred with 45 mg CDI (carbonyldiimidazole) in 3 ml of tetrahydrofuran for 3 h at 60° C. Then 30 mg diethanolamine (0.28 mmol) are added and the mixture is stirred overnight at ambient temperature. Then the mixture is evaporated down, the residue is taken up in ethyl acetate, washed with water and the organic phase is dried over sodium sulphate. Then it is concentrated by rotary evaporation.
Yield: 42 mg (34% of theory)
Rf=0.23 (silica gel, methylene chloride/methanol 9:1)
C25H29N3O5 (MW=451.52)
Mass spectrum: m/z=452 (M+H)+
The following compounds of formula I are prepared analogously to Example 4:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







4.001
Me
Ph




3.001 29.2
(M+H)+ = 421
0.12 (CH2Cl2/ MeOH 1:1)


 


4.002
Me
Ph




3.001 54.8
(M+H)+ = 449
0.27 (C)


 


4.003
Me
Ph




3.001 29.0
(M+H)+ = 364
0.24 (A)


 


4.004
Me
Ph




3.001 16.0
(M+H)+ = 438
0.16 (A)


 


4.005
Me
Ph




3.002 38.7
(M+H)+ = 378
0.35 (C)


 


4.006
Me
Ph




3.002 24.9
(M+H)+ = 440
0.33 (A)


 


4.007
Me
Ph




3.002 25.9
(M+H)+ = 392
0.54 (A)


 


4.008
Me
Ph




3.002 56.9
(M−H)− = 390
0.57 (A)


 


4.009
Me
Ph




3.002 59.0
(M+H)+ = 435
0.53 (C)


 


4.010
Me
Ph




3.002 90.2
(M+H)+ = 447
0.28 (A)


 


4.011
Me
Ph




3.002 26.2
(M+H)+ = 533
0.47 (A)


 


4.012
Me
Ph




3.002 47.5
(M+H)+ = 463
0.34 (C)


 


4.013
Me
Ph




3.001 14.8
(M+H)+ = 519
0.47 (A)


 


4.014
Me
Ph




3.002 51.0
(M+H)+ = 364
0.72 (A)









EXAMPLE 5
5-acetyl-3-[(4-aminomethyl-phenyl)-(3-dimethylamino-propylylamino)-methylidene]-2-indolinone




200 mg (0.51 mmol) 5-acetyl-3-[(4-cyano-phenyl)-(3-dimethylamino-propylamino)-methylidene]-2-indolinone (Example 1.054) are dissolved in 13 ml of methanolic ammonia, combined with 80 mg Raney nickel and hydrogenated at ambient temperature for 6 h at a pressure of 50 psi. Then the catalyst is filtered off and the solution is evaporated down. The residue is chromatographed through a silica gel column with methylene chloride:methanol 30:1. The desired fraction is collected and evaporated down.
Yield: 180 mg (89% of theory)
Rf=0.19 (silica gel, methylene chloride/methanol/conc. ammonia 9:1:0.1)
C23H28N4O2 (MW=392.5)
Mass spectrum: m/z=393 (M+H)+
The following compounds of formula I are prepared analogously to Example 5:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







5.001
Me








1.053 68.9
(M+H)+ = 408
0.39 (C)


 


5.002
Me








1.055 45.0
(M+H)+ = 364
0.5 (C)


 


5.003
Me




n-Pr
1.056 49.4
(M+H)+ = 350
0.44 (C)


 


5.004
Me








1.057 84.9
not determined
0.43 (C)


 


5.005
Me








1.058 57.4
(M+H)+ = 394
0.23 (C)


 


5.006
Me








1.062 88.6
(M+H)+ = 407
0.26 (C)


 


5.007
Me








1.059 68.7
(M+H)+ = 436
0.53 (C)









EXAMPLE 6
5-acetyl-3-{benzo[1.3]dioxol-5-yl-[3-(N-methyl-N-acetyl-amino)-propylamino]-methylene}-2-indolinone




150 mg (0.38 mmol) 5-acetyl-3-[benzo[1.3]dioxol-5-yl-(3-methylamino-propylamino)-methylidene]-2-indolinone (Example 2) are placed in 4 ml methylene chloride and combined with 54 μl triethylamine. 28 μl (0.39 mmol) acetylchloride are added dropwise to this solution while cooling with ice and the mixture is stirred for 10 min. Then the mixture is left to warm up to ambient temperature and stirred for 1 h. The solution is then washed with water, the organic phase is dried over sodium sulphate, suction filtered and concentrated by rotary evaporation. The residue is eluted through a silica gel column with ethyl acetate/cyclohexane/methanol 9:9:2. The desired fraction is collected and evaporated down.
Yield: 45 mg (27% of theory)
Rf=0.51 (silica gel, methylene chloride/methanol 9:1)
C24H25N3O5 (MW=435.478)
Mass spectrum: m/z=436 (M+H)+
The following compounds are prepared analogously to Example 6:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







6.001
Me
Ph




2.004 24.8
(M+H)+ = 440
0.30 (C)


 


6.002
Me
Ph




2.004 10.1
(M+H)+ = 450
0.45 (ethyl acetate/ MeOH 80:1)


 


6.003
Me








5.000 53.4
(M+H)+ = 435
0.30 (C)


 


6.004
Me








5.001 45.4
(M+H)+ = 450
0.54 (C)


 


6.005
Me








5.002 19.2
(M+H)+ = 406
0.41 (C)


 


6.006
Me




n-Pr
5.003 71.4
(M+H)+ = 392
0.53 (C)


 


6.007
Me








5.005 81.3
(M+H)+ = 436
0.35 (C)


 


6.008
Me








5.004 39.6
(M+H)+ = 478
0.56 (C)


 


6.009
Me








5.006 24.2
(M+H)+ = 449
0.21 (A)


 


6.010
Me








5.007 56.9
(M+H)+ = 478
0.50 (A)


 


6.011
Me
Ph




2.004 25.3
(M+H)+ = 414
0.28 (C)


 


6.012
Me
Ph




2.007 67.0
(M+H)+ = 454
0.41 (A)









EXAMPLE 7
5-acetyl-3-[(Pyrazin-2-yl)-isobutylamino-methylidene]-2-indolinone




80 mg (0.23 mmol) 1.5-diacetyl-3-[chloro-(pyrazin-2-yl)-methylidene]-2-indolinone (Ex. VII) in 4 ml of tetrahydrofuran are stirred for 2 h at ambient temperature with 0.05 ml triethylamine and 0.022 g isobutylamine. The acetyl-protected intermediate product is combined with 0.8 ml of conc. ammonia without purification and stirred for half an hour at ambient temperature. Then it is evaporated down and the residue is chromatographed through a silica gel column using methylene chloride/methanol 40:1 as eluant.
Yield: 29 mg (36% of theory)
Rf=0.56 (silica gel, methylene chloride/methanol 9:1)
C19H20N4O2 (MW=336.393)
Mass spectrum: m/z=337 (M+H)+
EXAMPLE 8
5-acetyl-3-[(pyridin-4-yl)-(isobutylamino)-methylidene]-2-indolinone




500 mg (1.55 mmol) 1.5-diacetyl-3-[(pyridin-4-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.24) in 2.4 ml hexamethyldisilazane are heated to 120° C. with 0.23 g 4-amino-1-methylpiperidine for 3 h. Then the mixture is left to cool and 10 ml of methanol and 32 mg sodium methoxide are added and the mixture is stirred for 1 h at ambient temperature. Then it is evaporated down and the residue is chromatographed through a silica gel column with methylene chloride/methanol 12:1 as eluant.
Yield: 160 mg (31% of theory)
Rf=0.56 (silica gel, methylene chloride/methanol 9:1)
C20H21N3O2 (MW=335.405)
Mass spectrum: m/z=336 (M+H)+
The following compound of formula I is prepared analogously to Example 8:






















Rf value






Educt
Mass
(silica






Yield
spectrum
gel)


Example
R1
R2
R3
[%]
(ES) m/z
(eluant)







8.001
Me








V.26 26.4
(M+H)+ = 463
0.58 (C)


 


8.002
Me








V.26 38.8
(M+H)+ = 420
0.60 (A)


 


8.003
Me








V.26 13.6
(M+H)+ = 449
0.49 (C)


 


8.004
Me








V.26 43.8
(M+H)+ = 464
0.54 (C)


 


8.005
Me








V.29 21.0
(M+H)+ = 493
0.41 (B)


 


8.006
Me








V.29 12.0
(M+H)+ = 436
0.85 (B)


 


8.007
Me








V.30 trimethyl- imidazole 70.0
(M+H)+ = 450
0.68 (C)


 


8.008
Me








V.30 trimethyl- imidazole 54.0
(M+H)+ = 513
0.68 (C)









EXAMPLE 9
5-acetyl-3-[furan-3-yl-isobutylamino-methylidene]-2-indolinone




200 mg (0.65 mmol) 1.5-diacetyl-3-[furan-3-yl-methoxy-methylidene]-2-indolinone (Ex. VI.23) are suspended in 5 ml of dimethylformamide and stirred for 2 h with 61 mg isobutylamine at ambient temperature. The acetyl-protected intermediate product is combined with 1 ml of conc. ammonia without purification and stirred at ambient temperature for 30 min. Then the mixture is evaporated down and the residue is chromatographed through a silica gel column with the eluant methylene chloride/methanol 4:1.
Yield: 78 mg (37% of theory)
Rf=0.2 (silica gel, methylene chloride/methanol 30:1)
C19H20N2O3 (MW=324.383)
Mass spectrum: m/z=325 (M+H)+
EXAMPLE 10
5-acetyl-3-[1-(N′,N′-dimethylhydrazino)-1-(4-trifluoromethyl-phenyl)-methylidene]-2-indolinone




0.2 g (0.4 mmol) 1.5-diacetyl-3-[(4-trifluoromethylphenyl)-ethoxy-methylidene]-2-indolinone (Ex. VI.8) are suspended in 4 ml of dimethylformamide and stirred with 0.038 ml dimethylhydrazine at ambient temperature for 5 h. Then 2 ml of 1 N sodium hydroxide solution are added and the mixture is stirred at ambient temperature for 30 min. The reaction mixture is poured onto 10 ml of water, the precipitate is filtered off and dried in the desiccator.
If desired the product may be purified through a silica gel column with methylene chloride/methanol 30:1 as eluant.
Yield: 0.11 g (57% of theory)
Rf=0.55 (silica gel, methylene chloride/methanol 9:1)
C20H18F3N3O2 (MW=389.371)
Mass spectrum: m/z=390 (M+H)+
The following compounds are prepared analogously to Example 10:




















educt




Example
R1
R2
R3
Yield [%]
Mass spectrum (ES) m/z
Rf value (silica gel) (eluant)







10.001
Me








VI.20 42.0
(M + H)+ = 358
0.59 (A)


 


10.002
Me








VI.19 36.0
(M + H)+ = 340
0.24 (A)


 


10.003
Me








VI.10 16.0
(M + H)+ = 352
0.48 (A)


 


10.004
Et








IV.3 81.0
(M + H)+ = 336
0.34 (A)


 


10.005
Me








VI.8 35.0
(M + H)+ = 466
0.54 (A)


 


10.006
Me
Et




III.3 63.0
(M + H)+ = 274
0.79 (A)


 


10.007
Me








VI.8 14.0
(M + H)+ = 438
0.50 (A)


 


10.008
Me








VI.8 45.0
(M + H)+= 404
0.41 (A)


 


10.009
Me








VI.8 43.0
(M + H)+= 466
0.43 (A)


 


10.010
Me








VI.8 29.0
(M + H)+ = 460
0.43 (A)


 


10.011
Me








VI.8 67.0
(M + H)+ = 480
0.54 (A)


 


10.012
Me
Et




III.3 53.0
(M + H)+ = 322
0.53 (A)


 


10.013
Me
Et




III.3 58.0
(M + H)+ = 350
0.40 (A)


 


10.014
Me
Et




III.3 62.0
(M + H)+ = 350
0.47 (A)


 


10.015
Me








VI.28 72.0
(M + H)+ = 316
0.67 (C)


 


10.016
Me








VI.29 42.0
(M + H)+ = 302
0.47 (C)









EXAMPLE 11
Coated Tablets Containing 75 mg of Active Substance

















1 tablet core contains:





active substance
75.0
mg



calcium phosphate
93.0
mg



corn starch
35.5
mg



polyvinylpyrrolidone
10.0
mg



hydroxypropylmethylcellulose
15.0
mg



magnesium stearate
1.5
mg




230.0
mg










Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.

















Weight of core:
230
mg



die:
9
mm, convex










The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg.
EXAMPLE 12
Tablets Containing 100 mg of Active Substance
Composition:

















1 tablet contains:





active substance
100.0
mg



lactose
80.0
mg



corn starch
34.0
mg



polyvinylpyrrolidone
4.0
mg



magnesium stearate
2.0
mg




220.0
mg










Method of Preparation:

The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

















Weight of tablet:
220
mg



Diameter:
10
mm, biplanar, facetted on both





sides and notched on one side.










EXAMPLE 13
Tablets Containing 150 mg of Active Substance
Composition:

















1 tablet contains:





active substance
150.0
mg



powdered lactose
89.0
mg



corn starch
40.0
mg



colloidal silica
10.0
mg



polyvinylpyrrolidone
10.0
mg



magnesium stearate
1.0
mg




300.0
mg










Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

















Weight of tablet:
300
mg



die:
10
mm, flat










EXAMPLE 14
Hard Gelatine Capsules Containing 150 mg of Active Substance


















1 capsule contains:






active substance

150.0
mg



corn starch (dried
approx.
180.0
mg



lactose (powdered)
approx.
87.0
mg



magnesium stearate

3.0
mg




approx.
420.0
mg










Preparation:

The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
















Capsule filling:
approx. 320 mg



Capsule shell:
size 1 hard gelatine capsule.










EXAMPLE 15
Suppositories Containing 150 ma of Active Substance

















1 suppository contains:





active substance
150.0
mg



polyethyleneglycol 1500
550.0
mg



polyethyleneglycol 6000
460.0
mg



polyoxyethylene sorbitan monostearate
840.0
mg




2,000.0
mg










Preparation:

After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
EXAMPLE 16
Suspension Containing 50 mg of Active Substance

















100 ml of suspension contain:





active substance
1.00
g



carboxymethylcellulose-Na-salt
0.10
g



methyl p-hydroxybenzoate
0.05
g



propyl p-hydroxybenzoate
0.01
g



glucose
10.00
g



glycerol
5.00
g



70% sorbitol solution
20.00
g



flavouring
0.30
g



dist. water
ad 100
ml










Preparation:

The distilled water is heated to 70° C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
EXAMPLE 17
Ampoules Containing 10 ma Active Substance
Composition:

















active substance
10.0
mg



0.01 N hydrochloric acid q.s.



double-distilled water
ad 2.0
ml










Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
EXAMPLE 18
Ampoules Containing 50 ma of Active Substance
Composition:

















active substance
50.0
mg



0.01 N hydrochloric acid q.s.



double-distilled water
ad 10.0
ml










Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

## Claims

1. Compounds of general formula




wherein
R1 denotes a straight-chain or branched C1-5-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or
an aryl group optionally substituted by a fluorine, chlorine or bromine atom,
while by an aryl group is meant a phenyl or naphthyl group,

R2 denotes a C1-7-alkyl or C3-7-cycloalkyl group,
a 5- or 6-membered heteroaryl group with one to three heteroatoms selected from the group N, S and O, while both the heteratoms and the substituents may be identical or different, optionally substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C1-3-alkyl or C1-3-alkoxy groups,
a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group,
a phenyl group, to which is anellated another phenyl ring or a 5- or 6-membered heteroaromatic ring with one to three heteroatoms selected from the group N, S and O, while the heteratoms may be identical or different, and the bicyclic group may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C1-3-alkyl or C1-3-alkoxy groups and the substituents may be identical or different, or
a phenyl group which may be substituted by one to three fluorine, chlorine, bromine or iodine atoms or by one to three C1-3-alkyl, nitro, cyano, amino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, phenylcarbonylamino, C1-3-alkylsulphonylamino, arylsulphonylamino, trifluoromethyl, C1-3 alkylsulphonyl, carboxy, C1-3-alkoxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, C1-3-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, hydroxycarbonyl-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl) -amino-C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkoxy, C1-3-alkyl -amino-carbonyl-C1-3-alkoxy,carboxy-C1-3-alkoxy, C1-3-alkyloxy-carbonyl-C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, C1-3-alkoxy-carbonylamino-C1-3-alkyl, amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3alkyl, C1-3-alkyl-carbonylamino-C1-3-alkyl, phthalimido, pyrrolyl or mono- or di-(C1-3-alkyl)-pyrrolyl groups, while the substituents are identical or different, and
R3 denotes a hydrogen atom,
a straight-chain or branched C1-6-alkyl group which may be substituted by one to three carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-(C1-3-alkyl)-amino-carbonyl, N-[di-(C1-3-alkyl) -amino-(C1-3-alkyl)]-N-(C1-3-alkyl)-amino-carbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-C1-3-alkyl-aminocarbonyl, heteroaryl-C1-3-alkyl-aminocarbonyl, N-(aryl)-N -(C1-3-alkyl)-aminocarbonyl, N-(heteroaryl)-N—(C1-3-alkyl)-aminocarbonyl, di-(ω-hydroxy -C2-3-alkyl)-aminocarbonyl, aryl or heteroaryl groups or by a 5 to 7-membered cyclo-alkyleneimino or cycloalkyleneiminocarbonyl group,
while in the above-mentioned cycloalkyleneimino or cycloalkyleneiminocarbonyl group a methylene group may be replaced in position 3 or 4 by an —NH—, —N(C1 -3-alkyl)- or —N(C1-4-alkoxy-carbonyl)- group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,

a straight-chain or branched C2-6-alkyl group which is substituted from position 2 onwards by one to three hydroxy, C1-3-alkoxy, aryloxy, heteroaryloxy, amino-C1-3-alkyloxy, C1-3-alkyl-amino-C1-3-alkyloxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, ω-hydroxy-C2-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, heteroaryl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, N—(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-4-alkoxy-carbonyl)-amino, arylcarbonylamino, N—(C1-3-alkyl)-N-(arylcarbonyl)-amino, (ω-hydroxy-C2-3-alkyl)-amino, di-(ω-hydroxy-C2-3-alkyl)-amino, arylamino, heteroarylamino, C1-3-alkylsulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino, (C1-3-alkyl-amino)-carbonyl-amino, [di-(C1-3-alkyl)-amino]-carbonyl-amino, (C1-3-alkyl-amino)-C1-3-alkyl-carbonyl-amino, [di-(C1-3-alkyl)-amino]-C1-3-alkyl-carbonyl-amino, N-(aryl-C1-3-alkyl-carbonyl)-N—(C1-3-alkyl)-amino, N—(C1-3-alkyl)-N—[(C1-3-alkyl-amino)-carbonyl]-amino or N—(C1-3-alkyl)-N—{[di-(C1-3-alkyl)-amino]-carbonyl}-amino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl-, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl-, aryl or heteroaryl group or by a 5 to 7-membered cyclo-alkyleneimino or cycloalkyleneiminocarbonyl group,
while in the above-mentioned cycloalkyleneimino or cycloalkyleneiminocarbonyl group a methylene group in position 3 or 4 may be replaced by an —N—, —N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)- group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,

a C2-4-alkenyl or C2-4-alkynyl group, while between the nitrogen atom to which R3 is bound and the multiple bond there is at least one sp3-hybridised carbon atom and the alkenyl or alkynyl group may be substituted by one to three C1-3-alkyl groups,
a C1-5-alkyl group in the methylene group which is adjacent to the nitrogen atom to which R3 is bound may be replaced by an —N—, or a —N(C1-3-alkyl)- group or by an oxygen atom,
a C1-4-alkyloxy group or
an amino group which may be substituted by one or two C1-3-alkyl, aryl, aryl-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-4-alkyloxy-carbonyl, arylcarbonyl or aryl-C1-3-alkyl-carbonyl groups, while the substituents may be identical or different,
while the above-mentioned alkyl groups may be straight-chain or branched,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

2. Compounds of general formula I according to claim 1, wherein
R2R3 defined as in claim 1 and
R1 denotes a methyl, ethyl, n-propyl, isopropyl, n-pentyl, trifluoromethyl or phenyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

3. Compounds of general formula I according to claim 2, wherein
R1 denotes a methyl or ethyl group,
R2 denotes an ethyl, propyl, butyl or pentyl group, a pyridinyl, furanyl or pyrazinyl group,
a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or
a phenyl group which may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or by one or two C1-3-alkyl, nitro, cyano, amino, C1-3-alkylcarbonylamino, phenylcarbonylamino, C1-3-alkylsulphonylamino, trifluoromethyl, carboxy, C1-3-alkoxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy, C1-3-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, hydroxycarbonyl-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkylaminocarbonyl, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, amino-C1-3-alkyl or C1-3-alkyl-carbonylamino-C1-3-alkyl groups, while the substituents are identical or different, and
R3 a hydrogen atom,
a straight-chain or branched C1-6-alkyl group which may be substituted by a carboxy, C1-4-alkoxy-carbonyl, phenyl, pyridinyl, indolyl, imidazolyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneimino-carbonyl group,
while the above-mentioned phenyl group may optionally be substituted by a nitro, cyano, C1-3-alkyloxy, [di-(C1-3-alkyl)-amino]-C1-3-alkyloxy, amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group and
in the above-mentioned cycloalkyleneimino and cycloalkyleneiminocarbonyl group a methylene group in position 3 or 4 may be replaced by an —N—,
—N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)- group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group,

a straight-chain or branched C2-6-alkyl group which is substituted from position 2 onwards by a hydroxy, C1-3-alkoxy, ω-hydroxy-C2-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-4-alkoxy-carbonyl)-amino, phenylcarbonyl-amino, N—(C1-3-alkyl)-N-(phenylcarbonyl)-amino, di-(ω-hydroxy-C2-3-alkyl)-amino, pyridinylamino, nitro-pyridinyl-amino, chloro-trifluoromethyl-pyridinylamino, C1-3-alkyl-sulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino or C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C1-4-alkoxy-carbonyl, phenyl, pyridinyl, imidazolyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(ω-hydroxy-C2-3-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cyclo-alkyleneiminocarbonyl group,
while in the above-mentioned cycloalkyleneimino or cycloalkyleneiminocarbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—,—N(C1-3-alkyl)- or —N(C1-4-alkoxy-carbonyl)- group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 may be replaced by a carbonyl group,
and the above-mentionedn phenyl groups may optionally be substituted by an amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group, or

or represent a propenyl or propynyl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

4. Compounds of general formula I according to claim 3, wherein
R1 denotes a methyl group,
R2 denotes an ethyl, propyl, butyl or pentyl group,
a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or
a phenyl group which may be substituted by one or two fluorine, chlorine or bromine atoms or by one or two trifluoromethyl, nitro, cyano, C1-3-alkoxy, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, amino-C1-3-alkyl or C1-3-alkyl-carbonylamino-C1-3-alkyl-groups, while the substituents are identical or different, and
R3 denotes a straight-chain or branched C1-5-alkyl group which may be substituted by a carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(2-hydroxy-ethyl)-aminocarbonyl, piperazinylcarbonyl, 4-(C1-3-alkyl)-piperazinyl-carbonyl, 4-(C1-4-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group,
while the phenyl group may optionally be substituted by a nitro, cyano, C1-3-alkyloxy, [di-(C1-3-alkyl)-amino]-C1-3-alkyloxy, amino-C1-3-alkyl or C1-4-alkoxy-carbonylamino-C1-3-alkyl group,

a C2-5-alkyl group which is terminally substituted by a hydroxy, C1-3-alkoxy, phenyloxy, 2-hydroxy-ethoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkyl-carbonylamino, N—(C1-3-alkyl)-N—(C1-3-alkyl-carbonyl)-amino, C1-4-alkoxy-carbonylamino, N—(C1-3-alkyl)-N—(C1-4-alkoxy-carbonyl)-amino, phenylcarbonylamino, N—(C1-3-alkyl)-N-(phenyl-carbonyl)-amino, pyridinylamino, nitro-pyridinyl-amino, di-(2-hydroxy-ethyl)-amino, 3-chloro-5 -trifluoromethyl-pyridin-2-yl-amino, C1-3-alkylsulphonylamino, N—(C1-3-alkyl)-N—(C1-3-alkylsulphonyl)-amino, C1-3-alkoxy-carbonyl-C1-3-alkyl-carbonylamino, indolyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, morpholinyl, piperazinyl or 4-(C13-alkyl)-piperazinyl group and may optionally additionally be substituted from position 1 onwards by a
carboxy, C1-4-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(2-hydroxy-ethyl)-aminocarbonyl, piperazinylcarbonyl, 4-(C1-3-alkyl)-piperazinyl-carbonyl, 4-(C1-4-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group, or
an amino group which may be substituted by one or two C1-3-alkyl, aryl, aryl-C1-3-alkyl, C1-3-alkyl-carbonyl, C1-4-alkyloxy-carbonyl, arylcarbonyl or aryl-C1-3-alkyl-carbonyl groups, while the substituents may be identical or different,
while the above-mentioned alkyl groups may be straight-chain or branched,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

5. Compounds of general formula I according to claim 4, wherein
R1 denotes a methyl group,
R2 denotes an ethyl, propy, butyl or pentyl group,
a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy or ethylenedioxy group, or
a phenyl group and
R3 denotes a C1-4-alkyl group which may be terminally substituted by a C1-4-alkoxy-carbonyl group, or
a C2-4-alkyl group which is terminally substituted by a C1-3-alkyl-carbonylamino, phenyl-carbonylamino, di-(C1-3-alkyl)-amino, phenyl, pyridinyl or C1-3-alkylsulphonylamino group,
while the above-mentioned alkyl groups may be straight-chain or branched,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

6. The following compounds of general formula I according to claim 1:
(a) 5 -acetyl-3 -[3 -(methoxycarbonylpropylamino)-(benzo- [1.3]dioxyo-5-yl)-methylidene]-2-indolinone




(b) 5-acetyl-3 -[isopropylamino-phenyl-methylidene]-2-indolinone




(c) 5-acetyl-3 -[propylamino-phenyl-methylidene]-2-indolinone




(d) 5-acetyl-3 -[(3 -methoxycarbonyl-propylamino)-(2.3 -dihydro-benzo [1.4]dioxin-6-yl)-methylidene]-2-indolinone




(e) 5 -acetyl-3 - [(benzo[1.3]dioxol-5-yl)-(3 -(benzoylamino-propylamino)-methylidene]-2-indolinone




(f) 5-acetyl-3 -[(benzo [1.3]dioxol-5 -yl)-(3 -(butyrylamino-propylamino)-methylidene]-2-indolinone




(g) 5-acetyl-3-[(3-methanesulphonylamino-propylamino)-phenyl-methylidene]-2-indolinone




(h) 5-acetyl-3-[1-(3.4-difluorophenyl)-1-(N′,N′-dimethylhydrazino)-methylidene]-2-indolinone




(i) 5-acetyl-3-[1-(4-dimethylamino-butyl)-butenylidene]-2-indolinone




(j) 5-acetyl-3-[1-phenyl-1-(3-pyridin-3-yl-propylamino)-methylidene]-2-indolinone





and the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

7. Physiologically acceptable salts of the compounds according to claim 1 with inorganic or organic acids or bases.

8. Pharmaceutical compositions containing a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids or bases optionally together with one or more inert carriers and/or diluents.

9. Process for preparing a pharmaceutical composition according to claim 8, characterised in that said compound is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

10. A method of treating type I and type II diabetes mellitus, diabetes associated disorders selected from diabetic neuropathy and degenerative neurological diseases selected from Alzheimer's disease, stroke, neurotraumatic injuries and bipolar disorders, said method comprised of the steps of administering to a patient in need therof an effective amount of a compound according to claim 1 or a pharmaceutically accapetable salt thereof.

11. Process for preparing the compounds of general formula I according to claims 1 comprised of the steps of:
a) reacting a compound of general formula




wherein R1 and R2 are defined as in claim 1,
R18 denotes a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
Z denotes a leaving group such as for example a halogen atom, a hydroxy, alkoxy, alkyl-sulphonyl, aralkylsulphonyl, or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy, methanesulphonyl, toluenesulphonyl or benzyloxy group,
with an amine of general formula


R3—NH2   (III),


wherein R3 is defined as in claim 1, while any hydroxy, amino or imino groups contained in the groups R2 and/or R3 may temporarily be protected by suitable protective groups,
said method further characterized in that:
in order to prepare a compound of formula I which contains an aminocarbonyl group, a compound which contains a carboxy group is reacted with the corresponding amine,
in order to prepare a compound of formula I which contains a carbonylamino group, a compound which contains an amino group is reacted with the corresponding acid chloride,
in order to prepare a compound of formula I which contains an aminomethyl group, a compound which contains a cyano group is hydrogenated to form the corresponding aminomethyl derivative,
in order to prepare a compound of formula I which contains an amino group, a compound which contains a nitro group is hydrogenated,
and/or
any protective groups which may be used during the reaction are then cleaved and/or
the compounds of general formula I thus obtained are resolved into their enantiomers and/or diastereomers and/or
the compounds of general formula I thus obtained are converted into their salts, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids or bases.